Many neural disorders are characterised by abnormal inhibitory neuron signalling and, in particular a lack of the neuro-transmitter γ-aminobutyric acid (GABA), secreted by inhibitory neurons. GABA, a metabolite of glutamate, is an inhibitory neurotransmitter which counteracts the effects of excitatory neurotransmitters. Excitatory neurotransmitters (typically acetylcholine, glutamate, or serotonin) open cation channels, causing an influx of Na+ that depolarises the postsynaptic membrane toward the threshold potential for firing an action potential and hence cause the propagation of a signal across the synapse. Inhibitory neurotransmitters, by contrast, open either Cl− channels or K+ channels, and this suppresses firing by making it harder for excitatory influences to depolarise the postsynaptic membrane.
Abnormal inhibitory function may contribute to symptoms of Parkinson's Disease and is fundamental to the pathology of several other neural disorders including Huntington's Disease, Schizophrenia, autism, chronic pain and many forms of Epilepsy. Epilepsy, in common with most such disorders, has no known cure and is treated with a range of drugs aimed at managing the symptoms. Therefore Epilepsy and its treatment result in a severe degradation of quality of life, measured in days of activity, pain, depression, anxiety, reduced vitality and insufficient sleep or rest (similar to arthritis, heart problems, diabetes, and cancer).
Epilepsy affects 50,000,000 people worldwide and sufferers have a mortality rate two to three times higher than that of the general population with the risk of sudden death being 24 times greater. In addition to personal suffering, epilepsy imposes an annual economic burden of $15.5 billion in the USA alone, in associated health care costs and losses in employment, wages, and productivity. Therefore any alternative or new therapy, especially one with the potential to be curative, would have very far reaching benefits.
Research aiming to enhance inhibitory neuron function by cell transplantation has focused on the use of multi-potent cells and immortalised neurons that have been genetically engineered to produce GABA (Bosch et al., (2004) Exp Neural 190, 42-58; Thompson, (2005) Neuroscience 133, 1029-37).
In order for the grafted cells to effectively reach affected regions and functionally integrate, it is necessary that the cells migrate away from the site of the graft and intermix with the host cells establishing inhibitory synapses with local excitatory neurons. A lack of migratory activity of the transplanted cells has been a flaw of previous attempts to derive new neural tissue from precursor cells, such as in the case of embryonic stem cell (ES)-derived neurons (Wernig et al., (2004) J Neurosci 24, 5258-68; Ruschenschmidt et al., (2005) Epilepsia 46 Suppl 5, 174-83) and genetically engineered GABA-producing cells (Bosch et al, supra.; Thompson, supra). ES-derived cells or other neural precursors transplanted into postnatal brains do not migrate extensively but form clumps of graft-derived cells in, or near, the site of transplantation (Bosch et al., supra; Ruschenschmidt et al., supra; Thompson, supra) and thus their value as a therapy is restricted, since usage would require multiple graft sites and only a limited volume of brain parenchyma can be modified. It is also unlikely that the grafted cells could be adequately positioned to effectively increase inhibition if the position of their cell body is constrained to the site of transplantation.
During development, cells from the medial ganglionic eminence form inhibitory interneurons. Studies on MGE cells are contradictory. One recent study (Olsson M et al. Neuroscience 69(4) 1169-82 (1995)) concluded that MGE cells have a relatively low migratory capacity, compared with other neural precursor cells, when transplanted into a host brain and that they would not be able to cross regions of the brain affected by neural disease, whereas the paper by Butt et al. (Neuron 48, 591-604, 2005) reported rapid migration.
ES cells have been shown to produce differentiated neurons in a host brain and so appear to be an excellent prospect for restoration of inhibitory neuron function in the diseased brain. However, ES-derived transplants also form a heterogenous population of cells—although roughly 14% of ES-derived cells grafted into the postnatal brain express GAD67 (a marker of GABA-containing interneurons), another 44% exhibit a glutaminergic phenotype, and so would be likely to have an excitatory function (the opposite to that desired), and an unknown number are presumably astrocytes (Wernig et al., supra). Also transplantation of ES-derived progenitor cells in order to increase GABAergic activity of the brain is fundamentally flawed, not only because of the limited migratory capacity of the cells, as mentioned above, but also because, following transplantation, formation of tumours is a common problem (Wernig et al., supra; Ruschenschmidt et al, supra).